At Work: Radiochemistry Service Chief Jason Lewis

I come from a family of farmers and ship-builders, who live in a little village in the south of England called Horndean. A career in science wasn't necessarily something my parents were familiar with, but they encouraged me to do whatever it was that made me happy, which, for me, was science.

In some ways I can trace my interest in science directly back to the launch of the first space shuttle in 1981. My middle school teacher at the time said that by the year 2000 anyone with a degree in science would be able to go into space. I told myself that I needed to get a science degree so I'd be ready. Needless to say, he was slightly off and I still haven't made it into space, but that did start the ball rolling for me.

For my undergraduate degree, I went to the University of Essex, in the east of England. I chose the program because it allowed students to do a degree by thesis rather than by examination. I was much more interested in doing hands-on research than I was learning from books. My undergraduate degree was in chemistry and I narrowed the focus of my doctoral research to biochemistry, which I studied at the University of Kent at Canterbury. Specifically, I was doing research in radiochemistry, the field I work in today.

To me, what was and still is most interesting about radiochemistry is that it provides opportunities to translate agents rapidly from the research bench to the clinic. The field encompasses many different disciplines, including chemistry, biology, and physics. My PhD research involved three years of intensive radiochemistry lab work, which eventually resulted in a thesis focused on the use of radiopharmaceuticals for imaging cancer.

The Benefits of Radiochemistry

Medical cyclotrons produce the radioisotopes used in PET scanning. Radiochemistry incorporates cyclotron-produced positron-emitting radionuclides into radiochemicals and radiopharmaceuticals. In combination with PET imaging, these radiopharmaceuticals are used as diagnostic agents, designed to delineate a physiological process associated with cancer in patients. Combining radiolabeled tracers and PET imaging can provide information on functional changes well ahead of the structural changes other imaging tools can identify.

The most important feature of PET radiochemistry is that the physical amount of diagnostic or therapeutic agent that we give patients is miniscule in comparison to what is given in, for example, chemotherapy.

For example, the sugar-based radiopharmaceutical fluoro-2-deoxy-D-glucose (FDG) remains the workhorse of the PET facilities given the excellent clinical utility and the widespread availability of this drug. If you took a single FDG dose given to a patient, you would need more than one million doses to equal a single teaspoon of sugar. Because you are using such miniscule amounts, there generally is not a pharmacologically negative effect when you give radiopharmaceuticals to patients.

The other advantage involves starting with an existing nonradioactive molecule that is used as a chemotherapeutic agent, for instance, to target breast cancer. In certain situations, we can take that molecule and swap out one of its atoms for a radioactiveatom. This allows us to image and track precisely where in the body and in the breast tumor that drug travels. And, moving forward, it will allow us to use noninvasive PET imaging to see how a patient will respond to therapy — before it is delivered. This, in turn, will allow us to truly tailor a treatment regimen on a patient-by-patient basis.

At a scientific conference during the final year of my PhD, I met Carolyn Anderson, who is now a professor of Radiology at Washington University School of Medicine in St. Louis. Carolyn offered me a postdoctoral position in her lab, and I jumped at the chance to work for both her and Professor Michael Welch, who, as the then-Director of Radiological Sciences at WashU, has often been referred to as the dean of radiochemistry. My plan at the time was to work with both of them for two years. But by the end of the two years, I had been offered a junior faculty position, which in turn became an assistant professor position, and I ended up staying for 11 years.

“ For me, the potential clinical application of my research is incredibly important. “

Jason Lewis, Radiochemistry Service Chief

During those years, I worked on identifying small molecules to target tumor hypoxia. When certain tumors grow, oftentimes portions of the tumor are cut off from the blood supply, leaving these areas with lower oxygen levels than surrounding healthy tissues. These hypoxic tumor cells are often more resistant to chemotherapy and radiation therapy. We tested various small molecules to target these hypoxic cells. In doing so, we demonstrated that a PET-imaging-based hypoxia measurement technique using a metallic-based small molecule tracer known as Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) was successful in predicting a cancer patient's response to therapy.

The hope is also that this small molecule can also be used to selectively target and kill the oxygen-deficient tumor cells. There are a number of recent papers investigating the clinical application of this molecule, and a multicenter clinical trial testing its use as a predictor of treatment response is set to begin soon.

The Lure of Translational Research

For me, the potential clinical application of my research is incredibly important. In fact, it was a major determinant in my decision, after more than a decade at Washington University, to come to Memorial Sloan Kettering Cancer Center, where there is such a strong emphasis placed on translational research. When I started here, it quickly became evident that Memorial is one of the leaders in bringing new radiopharmaceutical drugs into the clinic.

In addition to my joint appointments as Chief of the Radiochemistry Service and as an associate attending radiochemist in the Department of Radiology, I work closely with Dr. Steve Larson, who, as Chief of the Nuclear Medicine Service, will help translate the agents developed in my lab into clinical practice. Wearing all these hats allows me to have a greater impact on clinical success. I like being able to make decisions, and I don't mind having the buck stop with me. It helps that I have an incredibly supportive department chair in Dr. Hedvig Hricak and program chair in Dr. David Scheinberg.

The history here is remarkable. Memorial Sloan Kettering was one of the very first hospitals in the country to have its own medical cyclotron. It has been known for years for its sterling reputation in radiochemistry and translational work with PET imaging.

So far in my lab, we have a biologist, an organic chemist, an inorganic chemist, and a biochemist. It was important to me that the members of my lab had different backgrounds and expertise, which would allow them to compliment each other. To me, one of the most important aspects of being a faculty member is the training of the next generation of research scientists. It is vitally important to me that the postdoctoral fellows that come through my lab obtain a well-rounded education in all aspects of radiochemistry, molecular imaging, and translational science so that when they leave they are ready to run their own independent programs.

My lab has a number of projects ongoing. Working in collaboration with researchers from the University of Rhode Island and Yale University, one of our short-term goals is based on the discovery of the water-soluble peptide pH (Low) Insertion Peptide (pHLIP), which selectively targets cancer cells by exploiting the intrinsically low extracellular pH of tumors. We have already shown that the pH-dependent insertion of pHLIP within cell membranes allows for the targeting of tumors and the delivery of molecules to cancer cells by exploiting low extracellular pH. At the pH of normal healthy tissue, pHLIP weakly interacts with the surface of the cell membrane without insertion into it.

We have taken the pHLIP peptide and tagged it with 64Cu, and we have successfully PET-imaged tumors in vivo in mice. This agent will carry cargo across cell membranes — with these cargos having the potential to be cancer drugs or nanoparticles. It will hopefully overcome many of the delivery issues we've experienced with other drugs.

Another project my laboratory is focusing on is the collaboration with Steve Larson and Peter Smith-Jones, Technical Director of Targeted Radiotherapy at Memorial Sloan Kettering. Wearing my hat as Director of the Cyclotron, we are beginning to produce the PET nuclide Zirconium-89, which will be incorporated into Steve's antibody imaging program. Members of my lab are looking into the isolation, production, and chemistry of this nuclide. Then, in tandem with Steve's group, we will move into antibody work for hopeful translation into the clinic.

antibody (AN-tee-BAH-dee)

A protein made by plasma cells (a type of white blood cell) in response to an antigen (a substance that causes the body to make a specific immune response). Each antibody can bind to only one specific antigen. The purpose of this binding is to help destroy the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

atom (A-tum)

The smallest part of a substance that cannot be broken down chemically. Each atom has a nucleus (center) made up of protons (positive particles) and neutrons (particles with no charge). Electrons (negative particles) move around the nucleus. Atoms of different elements contain different numbers of protons, neutrons, and electrons.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

biochemist (BY-oh-KEH-mist)

A scientist who has special training in the study of the chemicals and processes that occur in all living things.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

blood (blud)

A tissue with red blood cells, white blood cells, platelets, and other substances suspended in fluid called plasma. Blood takes oxygen and nutrients to the tissues, and carries away wastes.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

breast (brest)

Glandular organ located on the chest. The breast is made up of connective tissue, fat, and breast tissue that contains the glands that can make milk. Also called mammary gland.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cancer (KAN-ser)

A term for diseases in which abnormal cells divide without control and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord. Also called malignancy.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cell (sel)

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

chemotherapeutic agent (KEE-moh-THAYR-uh-PYOO-tik AY-jent)

A drug used to treat cancer.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

chemotherapy (KEE-moh-THAYR-uh-pee)

Treatment with drugs that kill cancer cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

clinical (KLIH-nih-kul)

Having to do with the examination and treatment of patients.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

clinical trial (KLIH-nih-kul TRY-ul)

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical study.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

dose (dose)

The amount of medicine taken, or radiation given, at one time.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

drug (drug)

Any substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition. Also refers to a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

hypoxia (hy-POK-see-uh)

A condition in which there is a decrease in the oxygen supply to a tissue. In cancer treatment, the level of hypoxia in a tumor may help predict the response of the tumor to the treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

hypoxic (hy-POK-sik)

Having too little oxygen.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

imaging (IH-muh-jing)

In medicine, a process that makes pictures of areas inside the body. Imaging uses methods such as x-rays (high-energy radiation), ultrasound (high-energy sound waves), and radio waves.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

isolation (I-soh-LAY-shun)

State of being separated from others. Isolation is sometimes used to prevent disease from spreading.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

joint (joynt)

In medicine, the place where two or more bones are connected. Examples include the shoulder, elbow, knee, and jaw.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

medicine (MEH-dih-sin)

Refers to the practices and procedures used for the prevention, treatment, or relief of symptoms of a diseases or abnormal conditions. This term may also refer to a legal drug used for the same purpose.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

membrane (MEM-brayn)

A very thin layer of tissue that covers a surface.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

molecule (MAH-leh-kyool)

The smallest particle of a substance that has all of the physical and chemical properties of that substance. Molecules are made up of one or more atoms. If they contain more than one atom, the atoms can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

noninvasive (NON-in-VAY-siv)

In medicine, it describes a procedure that does not require inserting an instrument through the skin or into a body opening. In cancer, it describes disease that has not spread outside the tissue in which it began.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

nuclear medicine (NOO-klee-er MEH-dih-sin)

A branch of medicine that uses small amounts of radioactive substances to make pictures of areas inside the body and to treat disease. In cancer, the radioactive substance may be used with a special machine (such as a PET scanner) to find the cancer, to see how far it has spread, or to see how well a treatment is working. Radioactive substances may also be used to treat certain types of cancer, such as thyroid cancer and lymphoma.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

oxygen (OK-sih-jen)

A colorless, odorless gas. It is needed for animal and plant life. Oxygen that is breathed in enters the blood from the lungs and travels to the tissues.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

peptide (PEP-tide)

A molecule that contains two or more amino acids (the molecules that join together to form proteins). Peptides that contain many amino acids are called polypeptides or proteins.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radiation (RAY-dee-AY-shun)

Energy released in the form of particle or electromagnetic waves. Common sources of radiation include radon gas, cosmic rays from outer space, medical x-rays, and energy given off by a radioisotope (unstable form of a chemical element that releases radiation as it breaks down and becomes more stable).

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radioactive (RAY-dee-oh-AK-tiv)

Giving off radiation.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radiolabeled (RAY-dee-oh-LAY-buld)

Any compound that has been joined with a radioactive substance.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radiology (RAY-dee-AH-loh-jee)

The use of radiation (such as x-rays) or other imaging technologies (such as ultrasound and magnetic resonance imaging) to diagnose or treat disease.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radiopharmaceutical (RAY-dee-oh-FAR-muh-SOO-tih-kul)

A drug that contains a radioactive substance and is used to diagnose or treat disease, including cancer. Also called radioactive drug.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

radiotherapy (RAY-dee-oh-THAYR-uh-pee)

The use of high-energy radiation from x-rays, gamma rays, neutrons, protons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body near cancer cells (internal radiation therapy). Systemic radiotherapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that travels in the blood to tissues throughout the body. Also called irradiation and radiation therapy.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

regimen (REH-jih-men)

A treatment plan that specifies the dosage, the schedule, and the duration of treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

response (reh-SPONTS)

In medicine, an improvement related to treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

therapeutic (THAYR-uh-PYOO-tik)

Having to do with treating disease and helping healing take place.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

therapy (THAYR-uh-pee)

Treatment.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tissue (TIH-shoo)

A group or layer of cells that work together to perform a specific function.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tracer (TRAY-ser)

A substance (such as a radioisotope) used in imaging procedures.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

translation (trans-LAY-shun)

In biology, the process by which a cell makes proteins using the genetic information carried in messenger RNA (mRNA). The mRNA is made by copying DNA, and the information it carries tells the cell how to link amino acids together to form proteins.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

translational research (trans-LAY-shuh-nul reh-SERCH)

A term used to describe the process by which the results of research done in the laboratory are used to develop new ways to diagnose and treat disease.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tumor (TOO-mer)

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancer), or malignant (cancer). Also called neoplasm.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

will (wil)

A legal document in which a person states what is to be done with his or her property after death, who is to carry out the terms of the will, and who is to care for any minor children.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)